Mouse Model Of Cerebral Hypoperfusion Research Articles

Investigating APOE, APP-A\u03b2 metabolism genes and Alzheimer\u2019s disease GWAS hits in brain small vessel ischemic disease

Alzheimer’s disease and small vessel ischemic disease frequently co-exist in the aging brain. However, pathogenic links between these 2 disorders are yet to be identified. Therefore we used Taqman genotyping, exome and RNA sequencing to investigate Alzheimer’s disease known pathogenic variants and pathways: APOE ε4 allele, APP-Aβ metabolism and late-onset Alzheimer’s disease main genome-wide association loci (APOE, BIN1, CD33, MS4A6A, CD2AP, PICALM, CLU, CR1, EPHA1, ABCA7) in 96 early-onset small vessel ischemic disease Caucasian patients and 368 elderly neuropathologically proven controls (HEX database) and in a mouse model of cerebral hypoperfusion. Only a minority of patients (29%) carried APOE ε4 allele. We did not detect any pathogenic mutation in APP, PSEN1 and PSEN2 and report a burden of truncating mutations in APP-Aß degradation genes. The single-variant association test identified 3 common variants with a likely protective effect on small vessel ischemic disease (0.54>OR > 0.32, adj. p-value <0.05) (EPHA1 p.M900V and p.V160A and CD33 p.A14V). Moreover, 5/17 APP-Aß catabolism genes were significantly upregulated (LogFC > 1, adj. p-val<0.05) together with Apoe, Ms4a cluster and Cd33 during brain hypoperfusion and their overexpression correlated with the ischemic lesion size. Finally, the detection of Aβ oligomers in the hypoperfused hippocampus supported the link between brain ischemia and Alzheimer’s disease pathology.

Probiotic supplementation attenuates hippocampus injury and spatial learning and memory impairments in a cerebral hypoperfusion mouse model.

Probiotics are referred to species of living microscopic organisms may help conserve the normal balance of the digestive system and/or manage diseases. A number of autoimmune, psychiatric, cardiovascular and cerebrovascular disorders may be associated with the imbalance of gut microbiota. This study examines the effect of 21days consumption of multistrain probiotics on hippocampus injury, spatial and learning memory and some potential molecular mechanisms in a mouse model with cerebral hypoperfusion. Cerebral hypoperfusion was established in the mouse model by bilateral common carotid artery occlusion (BCCAO) for 20min and 24h reperfusion. Mixtures of several probiotic bacteria at concentrations of 107, 108 and 109CFU/day were orally administrated for 3weeks before the BCCAO. Spatial and learning memory, histological damage and apoptosis were assessed in the CA1, CA3 and dentate gyrus (DG) of the hippocampus 24h after ischemia. The malondialdehyde (MDA) content and brain-derived neurotrophic factor (BDNF) level were measured by ELISA technique. Prophylactic of probiotic considerably reduced the number of apoptotic cells and neuronal death in the CA1, CA3 and DG of the hippocampus at all three concentrations (P < 0.001). In addition, probiotics reduced spatial memory impairment and neurological dysfunction only at the 109-CFU/day (P < 0.01). Nonetheless, probiotics did not change the levels of BDNF and MDA in the hippocampus (P > 0.05). According to the findings, the daily prophylactic ingestion ofprobioticsreduced hippocampus damage and prevented the spatial learning and memory deficit by suppressing apoptosis in the mouse model with cerebral hypoperfusion. Probiotic supplementation may be suggested as a useful preventive dietary strategy for groups susceptible to cerebrovascular diseases.

White matter lesions, cerebral inflammation and cognitive function in a mouse model of cerebral hypoperfusion

Development of specific treatments for vascular dementia requires appropriate animal models. Bilateral carotid artery stenosis (BCAS) employs metal coils wrapped around both common carotid arteries to induce cerebral hypoperfusion, white matter lesions and memory impairment in mice. We focused on the relationship of memory impairment induced by BCAS to white matter lesions demonstrated by ex vivo magnetic resonance imaging (MRI). We found a significant effect of BCAS on perceptual learning in the novel object recognition test and on number of errors and latency to platform in the radial arm water maze. MRI analysis revealed a significant effect of BCAS on diffusion tensor imaging (DTI) parameters in white matter areas. After correction for multiple testing, significantly lower fractional anisotropy (FA) values were found in the corpus callosum and anterior commissure and significantly higher mean diffusivity values in the internal capsule. Focusing on the corpus callosum, we found that correlations between FA and number of errors on the RAWM test were significant after controlling for treatment. We further found that the effects of BCAS on cognition were partly mediated by its effects on white matter integrity. Immunofluorescence studies demonstrated significantly higher microglia cell density and soma size in the corpus callosum of BCAS mice compared to controls, and these parameters were correlated with the imaging data. The results of this study indicate that cognitive deficits induced by cerebral hypoperfusion due to BCAS result in part from microglia activation and disruption of white matter integrity, supporting the face and construct validity of this unique model of vascular dementia.

Astrocyte-specific overexpression of Nrf2 protects against optic tract damage and behavioural alterations in a mouse model of cerebral hypoperfusion

Mouse models have shown that cerebral hypoperfusion causes white matter disruption and memory impairment relevant to the study of vascular cognitive impairment and dementia. The associated mechanisms include inflammation and oxidative stress are proposed to drive disruption of myelinated axons within hypoperfused white matter. The aim of this study was to determine if increased endogenous anti-oxidant and anti-inflammatory signalling in astrocytes was protective in a model of mild cerebral hypoperfusion. Transgenically altered mice overexpressing the transcription factor Nrf2 (GFAP-Nrf2) and wild type littermates were subjected to bilateral carotid artery stenosis or sham surgery. Behavioural alterations were assessed using the radial arm maze and tissue was collected for pathology and transcriptome analysis six weeks post-surgery. GFAP-Nrf2 mice showed less pronounced behavioural impairments compared to wild types following hypoperfusion, paralleled by reduced optic tract white matter disruption and astrogliosis. There was no effect of hypoperfusion on anti-oxidant gene alterations albeit the levels were increased in GFAP-Nrf2 mice. Instead, pro-inflammatory gene expression was determined to be significantly upregulated in the optic tract of hypoperfused wild type mice but differentially affected in GFAP-Nrf2 mice. In particular, complement components (C4 and C1q) were increased in wild type hypoperfused mice but expressed at levels similar to controls in hypoperfused GFAP-Nrf2 mice. This study provides evidence that overexpression of Nrf2 in astrocytes exerts beneficial effects through repression of inflammation and supports the potential use of Nrf2-activators in the amelioration of cerebrovascular-related inflammation and white matter degeneration.

Photoacoustic imaging of cerebral hypoperfusion during acupuncture.

Using acupuncture to treat cerebral hypoperfusion is a hot topic. However, there is a lack of effective tools to clarify the therapeutic effect of acupuncture on cerebral hypoperfusion. Here, we show in a mouse model of cerebral hypoperfusion that photoacoustic tomography (PAT) can noninvasively image cerebral vasculature and track total hemoglobin (HbT) concentration changes in cerebral hypoperfusion with acupuncture stimulation on the YangLingQuan (GB34) point. We measured the changes of HbT concentration and found that the HbT concentration in hypoperfusion regions was clearly lower than that in the control regions when the acupuncture was absent; however, it was significantly increased when the acupuncture was implemented on the GB34 point. We also observed the increase of vessel size and the generation of new vessels in cerebral hypoperfusion during acupuncture. Laser speckle imaging (LSI) was employed to validate some of the PAT findings.

Restoration of oligodendrocyte pools in a mouse model of chronic cerebral hypoperfusion.

Chronic cerebral hypoperfusion, a sustained modest reduction in cerebral blood flow, is associated with damage to myelinated axons and cognitive decline with ageing. Oligodendrocytes (the myelin producing cells) and their precursor cells (OPCs) may be vulnerable to the effects of hypoperfusion and in some forms of injury OPCs have the potential to respond and repair damage by increased proliferation and differentiation. Using a mouse model of cerebral hypoperfusion we have characterised the acute and long term responses of oligodendrocytes and OPCs to hypoperfusion in the corpus callosum. Following 3 days of hypoperfusion, numbers of OPCs and mature oligodendrocytes were significantly decreased compared to controls. However following 1 month of hypoperfusion, the OPC pool was restored and increased numbers of oligodendrocytes were observed. Assessment of proliferation using PCNA showed no significant differences between groups at either time point but showed reduced numbers of proliferating oligodendroglia at 3 days consistent with the loss of OPCs. Cumulative BrdU labelling experiments revealed higher numbers of proliferating cells in hypoperfused animals compared to controls and showed a proportion of these newly generated cells had differentiated into oligodendrocytes in a subset of animals. Expression of GPR17, a receptor important for the regulation of OPC differentiation following injury, was decreased following short term hypoperfusion. Despite changes to oligodendrocyte numbers there were no changes to the myelin sheath as revealed by ultrastructural assessment and fluoromyelin however axon-glial integrity was disrupted after both 3 days and 1 month hypoperfusion. Taken together, our results demonstrate the initial vulnerability of oligodendroglial pools to modest reductions in blood flow and highlight the regenerative capacity of these cells.

The effect of vascular progenitor cells on chronic cerebral hypoperfusion mouse model

The effect of vascular progenitor cells on chronic cerebral hypoperfusion mouse model